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| United States Patent |
5,510,385
|
|
Stroppolo
, et al.
|
April 23, 1996
|
Pharmaceutical compositions containing the salts of
S(+)-2-(4-isobutylphenyl)propionic acid with basic aminoacids
Abstract
A pharmaceutical composition for oral use containing the salt of
S(+)-2-(4-isobutylphenyl)propionic acid with a basic aminoacid selected
between L-arginine and L-lysine is described.
| Inventors:
|
Stroppolo; Federico (Pregassona, CH);
Bonadeo; Daniele (Varese, IT);
Fornasini; Gian F. (Milan, IT);
Gazzaniga; Annibale (Rescaldina, IT)
|
| Assignee:
|
Zambon Group S.p.A. (Vicenza, IT)
|
| Appl. No.:
|
255945 |
| Filed:
|
June 7, 1994 |
Foreign Application Priority Data
| Jun 21, 1993[IT] | MI93A1324 |
| Current U.S. Class: |
514/555; 514/564; 514/565; 514/570 |
| Intern'l Class: |
A61K 031/205 |
| Field of Search: |
514/555,564,565,570
|
References Cited
U.S. Patent Documents
| 4689218 | Aug., 1987 | Gazzaniga et al. | 424/43.
|
| 4834966 | May., 1989 | Gazzaniga et al. | 424/43.
|
| 4994604 | Feb., 1991 | Tung et al.
| |
| 5009895 | Apr., 1991 | Lui | 424/465.
|
| 5200558 | Apr., 1993 | Kwan | 562/496.
|
| 5260337 | Nov., 1993 | Sims et al. | 514/570.
|
| Foreign Patent Documents |
| 2055683 | May., 1992 | CA.
| |
| 0424028A2 | Apr., 1991 | EP.
| |
| 0486045 | May., 1992 | EP.
| |
| 0505180 | Sep., 1992 | EP.
| |
Primary Examiner: Raymond; Richard L.
Attorney, Agent or Firm: Oblon, Spivak, McClelland, Maier & Neustadt
Claims
What we claim is:
1. A pharmaceutical composition comprising a salt of S(+)-Ibuprofen with a
basic aminoacid selected between L-arginine and L-lysine in an amount,
expressed as S(+)-Ibuprofen, of from 300 to 800 mg in admixture with a
pharmaceutically acceptable carrier.
2. A pharmaceutical composition according to claim 1 wherein amount of
S(+)-Ibuprofen salt is from 300 mg to 400 mg, expressed as S(+)-Ibuprofen.
3. A pharmaceutical composition according to claim 1 wherein the amount of
the S(+)-Ibuprofen salt corresponds to 400 mg of S(+)-Ibuprofen.
4. A pharmaceutical composition according to claim 1 wherein the
S(+)-Ibuprofen salt is S(+)-Ibuprofen arginate.
5. A pharmaceutical composition according to claim 1 wherein the
S(+)-Ibuprofen salt is S(+)-Ibuprofen lysinate.
6. The pharmaceutical composition as claimed in claim 1, consisting
essentially of said salt of S(+)-Ibuprofen, with said basic aminoacid and
said pharmaceutically acceptable carrier.
7. The pharmaceutical composition as claimed in claim 2, consisting
essentially of said salt of S(+)-Ibuprofen, with said basic aminoacid and
said pharmaceutically acceptable carrier.
8. The pharmaceutical composition as claimed in claim 3, consisting
essentially of said salt of S(+)-Ibuprofen, with said basic aminoacid and
said pharmaceutically acceptable carrier.
9. The pharmaceutical composition as claimed in claim 4, consisting
essentially of said salt of S(+)-Ibuprofen salt, and said pharmaceutically
acceptable carrier.
10. The pharmaceutical composition as claimed in claim 5, consisting
essentially of said salt of S(+)-Ibuprofen, and said pharmaceutically
acceptable carrier.
11. A method for the treatment of pathologies which combine moderate or
severe pain with inflammatory conditions comprising the administration of
a pharmaceutical composition comprising a salt of S(+)-Ibuprofen with a
basic aminoacid selected between L-arginine and L-lysine in an amount.,
expressed as S(+)-Ibuprofen, of from 300 to 800 mg in admixture with a
pharmaceutically acceptable carrier.
12. A method for the treatment of patients in need of therapies with high
doses of an analgesic and antiinflammatory agent comprising the
administration of a pharmaceutical composition comprising a salt of
S(+)-Ibuprofen with a basic aminoacid selected between L-arginine and
L-lysine in an amount, expressed as S(+)-Ibuprofen, of 300-400 mg in
admixture with a pharmaceutically acceptable carrier.
13. The method as claimed in claim 11, wherein said pharmaceutical
composition consists essentially of said salt of S(+)-Ibuprofen, with said
basic aminoacid and said pharmaceutically acceptable carrier.
14. The method as claimed in claim 12, wherein said pharmaceutical
composition consists essentially of said salt of S(+)-Ibuprofen, with said
basic aminoacid and said pharmaceutically acceptable carrier.
Description
The present invention relates to a pharmaceutical composition for opal use
containing a salt of S(+)-2-(4-isobutylphenyl)propionic acid with a basic
aminoacid and, mope particularly, it relates to a pharmaceutical
composition fop opal use containing the salt of
S(+)-2-(4-isobutylphenyl)propionic acid with a basic aminoacid selected
between L-arginine and L-lysine.
2-(4-Isobutylphenyl)propionic acid is a known non-steroidal
anti-inflammatory drug (Merck Index, XI Ed., no. 4812, page 776) whose
International Nonproprietary Name is Ibuprofen.
For the sake of clearness and simplicity, we report here below the
terminology which will be used in the present description, unless
differently specified, to indicate Ibuprofen, its enantiomeric forms and
its salts with basic aminoacids, together with the corresponding meanings:
Ibuprofen=racemic mixture of 2-(4-isobutylphenyl)propionic acid
S(+)-Ibuprofen=(S)-enantiomer of 2-(4-isobutylphenyl)propionic acid
R(-)-Ibuprofen=(R)-enantiomer of 2-(4-isobutylphenyl)propionic acid
Ibuprofen salt=salt of Ibuprofen with a basic aminoacid S(+)-Ibuprofen
salt=salt of S(+)-Ibuprofen with a basic aminoacid selected between
L-arginine and L-lysine
Ibuprofen arginate=salt of Ibuprofen with L-arginine
Ibuprofen lysinate=salt of Ibuprofen with L-lysine
S(+)-Ibuprofen arginate=salt of S(+)-Ibuprofen with L-arginine
S(+)-Ibuprofen lysinate=salt of S(+)-Ibuprofen with L-lysine.
Ibuprofen is widely used in therapy, for its analgesic, anti-inflammatory
and anti-pyretic properties, in the form of racemic mixture that is in the
form of a mixture 1:1 of the two enantiomers S(+)-Ibuprofen and
R(-)-Ibuprofen.
From some years, it is known that S(+)-Ibuprofen is the pharmacologitally
active enantiomer of Ibuprofen.
In the literature, it is also described that the use of S(+)-Ibuprofen
allows to obtain some therapeutic advantages in comparison with the
administration of an equivalent dose of Ibuprofen. International patent
application WO 89/00421 (Sunshine A. and Laska E. M.) describes, for
example, that S(+)-Ibuprofen has a faster, and consequently a longer,
analgesic effect than Ibuprofen.
Similarly, European patent application no. 424028 (Merck & Co. Inc.)
describes that the salts of S(+)-Ibuprofen with basic aminoacids such as
L-lysine, L-arginine, L-hystidine, D-lysine, D-arginine and D-hystidine
allow to obtain a faster and longer analgesic effect than Ibuprofen, than
Ibuprofen salts and than S(+)-Ibuprofen.
In the above cited European patent application no. 424028, the faster and
longer analgesic effect is described in particular in the case of the
salts of S(+)-Ibuprofen with L-lysine or D-tysine. The cited patent
applications suggest that the use of S(+)-Ibuprofen and particularly of
its salts with basic aminoacids represents an advantage in the case of the
analgesic treatment of moderate pains, such as pains consequent on oral
surgery, post-partum uterine cramps and dysmenorrhea, because of the
faster onset of the analgesic effect.
Furthermore, the literature suggests that such a therapeutic advantage is
particularly noticeable at low analgesic doses.
However, low doses of Ibuprofen, generally lower than or equal to 200 mg,
ape not therapeutically useful in the case of the analgesic treatment of
severe pains, especially when these ape associated to various inflammatory
conditions.
Therefore, there is a strong need of pharmaceutical compositions allowing
to efficiently and advantageously treat pathologies which combine moderate
and severe pains with more or less severe inflammatory conditions such as,
for example, osteoarthrosis and correlated syndromes, degenerative or
inflammatory rheumatic diseases, rheumatoid arthritis, ankylosing
spondylapthpitis, pepiapticulap and extra-auricular rheumatic diseases.
For the treatment of these particular diseases, which in the most cases
need a very long therapy, non-steroidal anti-inflammatory drugs are used
at high doses both as lap as the single dose and the daily dose ape
concerned.
For example, in the case of Ibuprofen, the therapeutic daily doses are from
600 mg to 1800 mg to be divided into one of more administrations.
We have now found that the salts of S(+)-Ibuprofen with basic amino-acids
and, in particular, the salts of S(+)-Ibuprofen with a basic aminoacid
selected between L-arginine and L-lysine, show particular therapeutic
advantages when administered by opal route at doses higher than 200 mg,
expressed as S(+)-Ibuprofen content.
Therefore, object of the present invention is a pharmaceutical composition
for opal use containing a salt of S(+)-Ibuprofen with a basic aminoacid
selected between L-arginine and L-lysine in an amount, expressed as
S(+)-Ibuprofen, higher than 200 mg in admixture with a pharmaceutically
acceptable carrier.
Preferably, the amount of S(+)-Ibuprofen salt is from 300 mg to 800 mg,
expressed as S(+)-Ibuprofen
Still more preferably, the amount of S(+)-Ibuprofen salt is equivalent to
300 mg or 400 mg of S(+)-Ibuprofen.
The pharmaceutical composition for oral use object of the present invention
can be in solid or liquid form.
Examples of pharmaceutical compositions in solid form are powders,
granulates, tablets and capsules.
Examples of pharmaceutical compositions in liquid form are aqueous
solutions, syrups and oral drops.
Dependently from the selected pharmaceutical form, the pharmaceutically
acceptable carrier may contain sweetening agents, flavouring agents,
diluents, disintegrating agents, lubricating agents and thickening agents.
Specific examples are sweetening agents such as saccharose, sorbitol,
mannitol, saccharin and aspartame, flavouring agents such as natural or
natural-like flavors, diluents such as sugars and celluloses,
disintegrating agents such as cross-linked polyvinylpyrrolidone, sodium
bicarbonate and sodium carbonate, lubricants such as magnesium stearate,
hydrogenated castor oil, polyethylen glycol, thickening agents such as
modified celluloses, polyvinylalcohol and polyvinylpyrrolidone.
Preferably, the pharmaceutical composition object of the present invention
is in solid form.
Still more preferably, the pharmaceutical composition object of the present
invention is in the form of optionally effervescent granulates or tablets.
The pharmaceutical compositions of the invention are prepared according to
conventional techniques.
As already underlined, the composition containing the S(+)-Ibuprofen salt
object of the present invention shows further therapeutic advantages which
make it different from the pharmaceutical compositions containing a lower
dose of active ingredient.
The compositions object of the invention allow to obtain an anticipation of
the onset of the pharmacological effect as reported in the literature.
Furthermore, the pharmaceutical compositions object of the invention allow
to reach maximum plasma concentration levels of S(+)-Ibuprofen
significantly much higher than those reached with a pharmaceutical
composition containing an equivalent dose of Ibuprofen.
As reported in Examples 6, 8 and 9, the values of the S(+)-Ibuprofen
maximum plasma concentrations obtained after oral administration of a
pharmaceutical composition according to the present invention containing
an amount of active ingredient corresponding to 400 mg or 300 mg of
S(+)-Ibuprofen, as S(+)-Ibuprofen arginate or lysinate, are about 15-20%
higher than those obtained after oral administration of an analogous
composition containing an amount of active ingredient corresponding to 800
mg or 600 mg, respectively, of Ibuprofen, as Ibuprofen arginate or
lysinate.
It is worth underlining that, after oral administration of a composition
containing S(+)-Ibuprofen arginate or lysinate, in an amount corresponding
to 200 mg of S(+)-Ibuprofen, the obtained values of maximum plasma
concentration are substantially equal to those obtained after
administration of an equivalent amount of Ibuprofen arginate or lysinate,
respectively (see Examples 7 and 10).
In other words, the maximum plasma concentrations of S(+)-Ibuprofen
obtained after administration of 200 mg of S(+)-Ibuprofen in the form of
arginine or lysine salt are the same as those obtained by measuring the
S(+)-Ibuprofen maximum plasma concentrations after administration of 400
mg of racemic Ibuprofen in the form of arginine or lysine salt.
On the contrary, the levels of S(+)-Ibuprofen maximum plasma concentrations
obtained after administration of 300 mg or 400 mg of S(+)-Ibuprofen in the
form of arginine or lysine salt are significantly higher than those
obtained by measuring the S(+)-Ibuprofen maximum plasma concentration
after administration of 600 mg or 800 mg respectively of racemic Ibuprofen
in the form of arginine or lysine salt.
This means that the pharmacological effect of the S(+)-Ibuprofen salt, when
orally administered at doses higher than 200 mg, expressed as
S(+)-Ibuprofen content, is significantly higher than that obtained with an
equivalent amount of S(+)-Ibuprofen in the form of the corresponding
Ibuprofen salt.
The effect of the compositions object of the present invention was
evaluated also in a double blind, randomized study carried out on patients
treated with a single dose.
A group of patients was treated with an aqueous solution containing 400 mg
of S(+)-Ibuprofen, as S(+)-Ibuprofen arginate, and a second group of
patients was treated with an aqueous solution containing 800 mg of
Ibuprofen, as Ibuprofen arginate.
The patients suffered from acute or moderate pains consequent on
stomatologic surgery (dental extraction).
The rate of onset of the analgesic effect and its efficacy were evaluated
by considering the pain intensity and the degree of pain attenuation after
0.5, 1, 1.5, 2, 3, 4, 5 and 6 hours after the administration and by timing
the moment of pain disappearance. The obtained results showed a
significant improvement of the therapeutic advantages obtained with the
administration of a composition according to the present invention with
respect to those obtained with the administration of the comparison
pharmaceutical composition.
In this regard, it is important to insist on the fact that the improved
effect is peculiar to the compositions containing an S(+)-Ibuprofen salt
according to the present invention, that is compositions with an
S(+)-Ibuprofen content higher than 200 mg; known pharmaceutical
compositions containing amounts of S(+)-Ibuprofen, in the form of a salt,
lower than or equal to 200 mg do not show such an improved effect.
From a practical point of view, this allows to significantly decrease the
doses to be administered to patients in need of therapies with high doses
while maintaining the same therapeutic effect, with a consequent lower
risk of side effects and toxicity.
It is evident how this represents a remarkable therapeutic advantage mainly
as far as therapies requiring the administration of high doses of active
ingredient, repeated more times during the day and for prolonged time
periods are concerned.
In order to better illustrate the present invention the following examples
are now given.
EXAMPLE 1
Preparation of a granulate containing S(+)-Ibuprofen arginate
S(+)-Ibuprofen arginate (738 g) was sieved and put in a mixer. Saccharose
(2162 g) and flavour (100 g) were added. After mixing, the granulate was
shared into sachets (3 g each) so that the content of S(+)-Ibuprofen per
sachet was 400 mg. Alternatively, the granulate was shared into sachets
containing 1.5 g or 2.25 g so that the content of S(+)-Ibuprofen per
sachet was 300 mg.
By working in the same way, sachets containing 1.5 g corresponding to 200
mg of S(+)-Ibuprofen were prepared as reference.
EXAMPLE 2
Preparation of a reference granulate containing Ibuprofen arginate
Ibuprofen arginate (1476 g) was sieved and put in a mixer. Saccharose (1324
g) and flavour (100 g) were added. After mixing, the granulate was shared
into sachets (3 g each) so that the content of Ibuprofen per sachet was
800 mg. Alternatively, the granulate was shared into sachets each
containing 1.5 g or 2.25 g so that the content of Ibuprofen per sachet was
400 mg or 600 mg respectively.
EXAMPLE 3
Preparation of tablets containing S(+)-Ibuprofen arginate
S(+)-Ibuprofen arginate (738 g) was sieved and put in a mixer with sodium
bicarbonate (300 g) cross-linked polyvinylpyrrolidone (60 g) and magnesium
stearate (8 g).
After mixing, the granulate was compressed into tablets each weighing 1106
mg so that each tablet contained 400 mg of S(+)-Ibuprofen.
EXAMPLE 4
Preparation of a granulate containing S(+)-Ibuprofen lysinate
By working as described in Example 1 but substituting S(+)-ibuprofen
arginate with an equivalent amount of S(+)-Ibuprofen lysinate, sachets
containing an amount of S(+)-Ibuprofen corresponding to 400 mg or 300 mg
and reference sachets containing an amount of S(+)-Ibuprofen corresponding
to 200 mg were prepared.
EXAMPLE 5
Preparation of a reference granulate containing Ibuprofen lysinate
By working as described in Example 2 but substituting Ibuprofen arginate
with an equivalent amount of Ibuprofen lysinate, sachets containing an
amount of Ibuprofen corresponding to 800 mg, 400 mg or 600 mg were
prepared.
EXAMPLE 6
Comparison between S(+)-Ibuprofen arginate and Ibuprofen arginate (400 mg
versus 800)
Aqueous solutions (100 ml) of a granulate containing 400 mg of
S(+)-Ibuprofen as S(+)-Ibuprofen arginate (Preparation A-1), prepared as
described in Example 1, and aqueous solutions (100 ml) of a granulate
containing 800 mg of Ibuprofen as Ibuprofen arginate (Preparation B-1),
prepared as described in Example 2, were administered in a single oral
dose to 7 subjects with an average age of 35.2 years.
Each subject was apparently healthy, especially as lap as the Renal,
hepatic and hematopoietic functions were concerned.
For the trial, a cross-over design was adopted: each subject received both
preparations in two treatment sessions carried out in two different weeks
randomizing the order of the administration. During each of the two
sessions, basal samples of venous blood were withdrawn in the morning to
each subject in fasting conditions, before administering Preparation A-1
or Preparation B-1.
Further, samples of venous blood were withdrawn at 5, 10, 15, 30, 45, 60,
90, 120, 240 and 480 minutes after the treatment. Plasma was then prepared
by centrifugation and preserved at -20.degree. C. until the analysis.
The analytical determination of the active ingredient in the plasma samples
was carried out by HPLC method as described hereinafter. Chromatographic
conditions:
Apparatus: JASCO BIP-1 with U.V. detector UVI DEC-100 v
Column: Chiral AGP, 100.times.4.0 mm, 5 .mu.m (Chron Tech) with a precolumn
Chiral AGP 10.times.3.0 mm (Chron Tech)
Mobile phase: 0.001M N,N-dimethyloctylamine in 0.02N sodium hydrogen
phosphate:acetonitrile=99:1, pH 6.5 with NaOH 6M
Flow: 1.2 ml/min
Wavelength: 230 nm
Internal standard: a solution of propyl p.hydroxybenzoate in acetonitrile
and phosphate buffer 0.01M pH 7.4.
HCl 3N (150 .mu.l ), internal standard solution (50 .mu.l ) and phosphate
buffer 0.01M pH 7.4 (31.25 .mu.l ) were added to plasma (250 .mu.l ).
Cyclohexane (5 ml) was added to the solution and, after mixing for 15
minutes and centrifugation at 3500 rpm, the upper phase was separated (3
ml) and the extraction was repeated.
After evaporation of the solvent, the residue was dissolved in phosphate
buffer 0.01M pH 7.4 (250 .mu.l ).
The solution (50 .mu.l ) was injected into the chromatograph.
Under the described operative conditions the retention times (RT) are the
following:
______________________________________
R(-)-Ibuprofen RT = 3.5 minutes
S(+)-Ibuprofen RT = 4.8 minutes
Internal standard RT = 10.2 minutes
______________________________________
The obtained results are reported in the following table 1.
TABLE 1
______________________________________
Mean plasma concentrations of S(+)-Ibuprofen after oral
treatment with a solution (100 ml) obtained by dissolution of a
sachet containing 400 mg of S(+)-Ibuprofen, in the form of
S(+)-Ibuprofen arginate (treatment A-1), according to the
present invention, and after oral treatment with a solution
(100 ml) obtained by dissolution of a sachet containing 800 mg
of Ibuprofen, in the form of Ibuprofen arginate (treatment
B-1).
S(+)-Ibuprofen plasma
concentrations (.mu.g/ml)
Sampling times
(minutes) Treatment A-1
Treatment B-1
______________________________________
0 0 0
5 19.09 13.65
10 32.35 25.83
15 34.40 28.63
30 35.11 28.91
45 31.61 31.41
60 30.50 27.75
90 25.30 23.67
120 18.16 18.91
240 6.90 10.80
480 2.41 2.74
______________________________________
Bioavailability parameters
The following parameters were calculated:
the area under curve of S(+)-Ibuprofen plasma concentration from time
"zero" to time 480 minutes (AUC.sub.obs =AUC.sub.o.fwdarw.480), expressed
as .mu.g.times.min.times.ml.sup.-1, was calculated according to the
trarezoidal method (gibaldi M. and Perrier D., "Pharmacokinetics", pages
293-296, Marcel Dekker Inc., New York 1975).
the area under curve of S(+)-Ibuprofen plasma concentration from time
"zero" to "infinite" (AUC.sub.tot) was calculated by the following
formula: AUC.sub.tot =AUC.sub.o.fwdarw.480 +AUC.sub.480.fwdarw.- wherein
AUC.sub.480- =concentration at 480 minutes/K.sub.e. and K.sub.e
=elimination constant
mean peak time (t.sub.max), expressed as minutes, was obtained from the
average of each peak time
the mean peak of maximum plasma concentration (C.sub.max), expressed as
.mu.g/ml, was calculated by the average of each concentration peak value.
The values of the bioavailability parameters are reported in the following
table 2.
TABLE 2
______________________________________
Mean values of the bioavailability parameters obtained after
oral treatment with preparation A-1, containing 400 mg of
S(+)-Ibuprofen (treatment A-1) and after oral treatment with
preparation B-1, containing 800 mg of Ibuprofen (treatment
B-1).
Bioavailability parameters
Treatment A-1
Treatment B-1
______________________________________
AUC.sub.obs (.mu.g .times. min .times. ml.sup.-1)
6072 6141
AUC.sub.tot (.mu.g .times. min .times. ml.sup.-1)
5662 6749
t.sub.max (min) 32.5 35.0
C.sub.max (.mu.g/ml)
40.4 34.3.sup.( *.sup.)
______________________________________
.sup.(*.sup.) the C.sub.max value reached with treatment A1 resulted to b
significantly higher than that reached with treatment B1.
The pharmacokinetic data clearly show that S(+)-Ibuprofen derived from
treatment A-1 (administration of a pharmaceutical composition according to
the present invention) was absorbed more rapidly, mainly during the first
minutes after the administration, than the S(+)-Ibuprofen deriving from
treatment B-1 and, furthermore, it reached plasma concentrations
(C.sub.max) significantly much higher than the concentrations obtained
with the reference treatment (treatment B-1).
EXAMPLE 7
Comparison between S(+)-Ibuprofen arginate and Ibuprofen arginate (200 mR
versus 400 mg)
The experimental design described in Example 6 was repeated by
administering aqueous solutions (100 ml) of a granulate containing 200 mg
of S(+)-Ibuprofen as S(+)-Ibuprofen arginate (Preparation R-1), prepared
as described in Example 1, and aqueous solutions (100 ml) of a granulate
containing 400 mg of Ibuprofen as Ibuprofen arginate (Preparation R-2),
prepared as described in Example 2. The values of S(+)-Ibuprofen plasma
concentration obtained after oral administration of Preparation R-1
(Treatment R-1) and after oral administration of Preparation R-2
(Treatment R-2) are reported in the following table 3.
TABLE 3
______________________________________
Mean plasma concentrations of S(+)-Ibuprofen after oral
treatment with Preparation R-1, containing 200 mg of S(+)-
Ibuprofen in the form of S(+)-Ibuprofen arginate (treatment
R-1) and after oral treatment with Preparation R-2, containing
400 mg of Ibuprofen in the form of Ibuprofen arginate
(treatment R-2).
S(+)-Ibuprofen plasma
concentrations (.mu.g/ml)
Sampling times
(minutes) Treatment R-1
Treatment R-2
______________________________________
0 0 0
5 10.26 8.92
10 18.15 16.89
15 21.03 17.87
30 20.72 18.29
45 18.07 18.01
60 15.52 16.07
90 12.47 13.46
120 9.82 11.57
240 3.94 4.52
480 1.07 1.69
______________________________________
The values of the bioavailability parameters are reported in the following
table 4.
TABLE 4
______________________________________
Mean values of the bioavailability parameters obtained after
oral treatment with preparation R-1, containing 200 mg of
S(+)-Ibuprofen (treatment R-1) and after oral treatment with
preparation R-2, containing 400 mg of Ibuprofen (treatment
R-2).
Bioavailability parameters
Treatment R-1
Treatment R-2
______________________________________
AUC.sub.obs (.mu.g .times. min .times. ml.sup.-1)
3249 3490
AUC.sub.tot (.mu.g .times. min .times. ml.sup.-1)
3420 3772
t.sub.max (min) 22.5 27.5
C.sub.max (.mu.g/ml)
23.09 21.55.sup.( *.sup.)
______________________________________
.sup.(*.sup.) the C.sub.max value reached with treatment R1 resulted to b
not significantly different from that reached with treatment R2.
Also the other pharmacokinetic parameters referred to S(+)-Ibuprofen
obtained with treatment R-1 do not significantly differ from those
obtained with treatment R-2.
A trend towards an anticipated absorption of S(+)-Ibuprofen derived from
treatment R-1 in comparison with that derived from treatment R-2 can be
noted.
EXAMPLE 8
Comparison between S(+)-Ibuprofen lysinate and Ibuprofen lysinate (400 mg
versus 800 mg)
The experimental design described in Example 6 was repeated by
administering aqueous solutions (100 ml) of a granulate containing 400 mg
of S(+)-ibuprofen as S(+)-Ibuprofen lysinate (Preparation A-2), prepared
as described in Example 4, and aqueous solutions (100 ml) of a granulate
containing 800 mg of Ibuprofen as Ibuprofen lysinate (Preparation B-2),
prepared as described in Example 5. The values of S(+)-Ibuprofen plasma
concentration obtained after oral administration of Preparation A-2
(Treatment A-2) and after oral administration of Preparation B-2
(Treatment B-2) are reported in the following table 5.
TABLE 5
______________________________________
Mean Plasma concentrations of S(+)-Ibuprofen after oral
treatment with Preparation A-2, containing 400 mg of S(+)-
Ibuprofen in the form of S(+)-Ibuprofen lysinate (treatment
A-2) and after oral treatment with Preparation B-2, containing
800 mg of Iguprofen in the form of Ibuprofen lysinate
(treatment B-2).
S(+)-Ibuprofen plasma
concentrations (.mu.g/ml)
Sampling times
(minutes) Treatment A-2
Treatment B-2
______________________________________
0 0 0
5 18.5 10.1
10 33.4 22.4
15 35.6 25.1
30 37.3 30.0
45 32.5 31.4
60 30.0 27.8
90 25.2 26.4
120 19.0 23.3
240 7.33 12.6
480 3.09 4.93
______________________________________
The values of the bioavailability parameters are reported in the following
table 6.
TABLE 6
______________________________________
Mean values of the bioavailability parameters obtained after
oral treatment with preparation A-2, containing 400 mg of
S(+)-Ibuprofen (treatment A-2) and after oral treatment with
preparation B-2, containing 800 mg of Ibuprofen (treatment
B-2).
Bioavailability parameters
Treatment A-2
Treatment B-2
______________________________________
AUC.sub.obs (.mu.g .times. min .times. ml.sup.-1)
6180 7200
AUC.sub.tot (.mu.g .times. min .times. ml.sup.-1)
6734 8295
t.sub.max (min) 32.0 45.5
C.sub.max (.mu.g/ml)
37.8 30.7.sup.( *.sup.)
______________________________________
.sup.(*.sup.) the C.sub.max value reached with treatment A2 resulted to b
significantly higher than that reached with treatment B2.
The pharmacokinetic data clearly show that S(+)-Ibuprofen derived from
treatment A-2 (administration of a pharmaceutical composition according to
the present invention) was absorbed more rapidly, mainly during the first
minutes after the administration, than the S(+)-Ibuprofen deriving from
treatment B-2 and, furthermore, it reached plasma concentrations
(C.sub.max) significantly much higher than the concentrations obtained
with the reference treatment (treatment B-2).
EXAMPLE 9
Comparison between S(+)-Ibuprofen lysinate and Ibuprofen lysinate (300 mg
versus 600 mg)
The experimental design described in Example 6 was repeated by
administering aqueous solutions (100 ml) of a granulate containing 300 mg
of S(+)-Ibuprofen as S(+)-Ibuprofen lysinate (Preparation A-3), prepared
as described in Example 4, and aqueous solutions (100 ml) of a granulate
containing 600 mg of Ibuprofen as Ibuprofen lysinate (Preparation B-3),
prepared as described in Example 5.
The values of S(+)-Ibuprofen plasma concentration obtained after opal
administration of Preparation A-3 (Treatment A-3) and after oral
administration of Preparation B-3 (Treatment B-3) are reported in the
following table 7.
TABLE 7
______________________________________
Mean plasma concentrations of S(+)-Ibuprofen after oral
treatment with Preparation A-3, containing 300 mg of S(+)-
Ibuprofen in the form of S(+)-Ibuprofen lysinate (treatment
A-3) and after oral treatment with Preparation B-3, containing
600 mg of Ibuprofen in the form of Ibuprofen lysinate
(treatment B-3).
S(+)-Ibuprofen plasma
concentrations (.mu.g/ml)
Sampling times
(minutes) Treatment A-3
Treatment B-3
______________________________________
0 0 0
5 13.9 8.0
10 25.1 19.6
15 26.7 20.3
30 29.0 21.2
45 24.4 22.6
60 21.5 20.8
90 17.0 19.0
120 14.3 17.5
240 6.72 8.64
480 2.15 3.71
______________________________________
The values of the bioavailability parameters are reported in the following
table 8.
TABLE 8
______________________________________
Mean values of the bioavailability parameters obtained after
oral treatment with preparation A-3, containing 300 mg of
S(+)-Ibuprofen (treatment A-3) and after oral treatment with
preparation B-3, containing 600 mg of Ibuprofen (treatment
B-3).
Bioavailability parameters
Treatment A-3
Treatment B-3
______________________________________
AUC.sub.obs (.mu.g .times. min .times. ml.sup.-1)
4615 5250
AUC.sub.tot (.mu.g .times. min .times. ml.sup.-1)
4703 6180
t.sub.max (min) 28.3 44.6
C.sub.max (.mu.g/ml)
31.0 24.2.sup.( *.sup.)
______________________________________
.sup.(*.sup.) the C.sub.max value reached with treatment A3 resulted to b
significantly higher than that reached with treatment B3.
The pharmacokinetic data clearly show that S(+)-Ibuprofen derived from
treatment A-3 (administration of a pharmaceutical composition according to
the present invention) was absorbed more rapidly, mainly during the first
minutes after the administration, than the S(+)-Ibuprofen deriving from
treatment B-3 and, furthermore, it reached plasma concentrations
(C.sub.max) significantly much higher than the concentrations obtained
with the reference treatment (treatment B-3).
EXAMPLE 10
Comparison between S(+)-Ibuprofen lysinate and Ibuprofen lysinate (200 mg
versus 400 mg)
The experimental design described in Example 6 was repeated by
administering aqueous solutions (100 ml) of a granulate containing 200 mg
of S(+)-Ibuprofen as S(+)-Ibuprofen lysinate (Preparation R-3), prepared
as described in Example 4 and aqueous solutions (100 ml) of a granulate
containing 400 mg of Ibuprofen as Ibuprofen lysinate (Preparation R-4),
prepared as described in Example 5. The values of S(+)-Ibuprofen plasma
concentration obtained after opal administration of Preparation R-3
(Treatment R-3) and after opal administration of Preparation R-4
(Treatment R-4) are reported in the following table 9.
TABLE 9
______________________________________
Mean plasma concentrations of S(+)-Ibuprofen after oral
treatment with Preparation R-3, containing 200 mg of S(+)-
Ibuprofen in the form of S(+)-Ibuprofen lysinate (treatment
R-3) and after oral treatment with Preparation R-4, containing
400 mg of Ibuprofen in the form of Ibuprofen lysinate
(treatment R-4).
S(+)-Ibuprofen plasma
concentrations (.mu.g/ml)
Sampling times
(minutes) Treatment R-3
Treatment R-4
______________________________________
0 0 0
5 11.0 8.13
10 17.9 16.0
15 21.2 20.3
30 19.8 20.8
45 17.5 17.7
60 15.8 17.3
90 11.9 14.3
120 10.0 12.1
240 5.31 7.03
480 1.90 2.25
______________________________________
The values of the bioavailability parameters are reported in the following
table 10.
TABLE 10
______________________________________
Mean values of the bioavailability parameters obtained after
oral treatment with preparation R-3, containing 200 mg of
S(+)-Ibuprofen (treatment R-3) and after oral treatment with
preparation R-4, containing 400 mg of Ibuprofen (treatment
R-4).
Bioavailability parameters
Treatment R-3
Treatment R-4
______________________________________
AUC.sub.obs (.mu.g .times. min .times. ml.sup.-1)
3410 4074
AUC.sub.tot (.mu.g .times. min .times. ml.sup.-1)
3698 4560
t.sub.max (min) 14.8 28.5
C.sub.max (.mu.g/ml)
22.3 21.0.sup.( *.sup.)
______________________________________
.sup.(*.sup.) the C.sub.max value reached with treatment R3 resulted to b
not significantly different from that reached with treatment R4.
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